The fungus Candida albicans commonly colonizes the epithelial surfaces of the body, with the alimentary canal considered as the primary site of colonization. Oropharyngeal candidiasis (OPC) results from fungal overgrowth and penetration of oral epithelium when the body's physical and immunological defenses are compromised in some way. OPC is commonly seen in AIDS and diabetes. Impairment of salivary gland function by disease or medical treatment is correlated with a high incidence of OPC. Growth of C. albicans on mucosal surfaces as a biofilm contributes to the lack of success of antifungal therapy and leads to recurrent infections. Therefore, novel therapeutic approaches are needed to prevent and treat OPC. Preliminary studies demonstrate the efficacy of photodynamic therapy (PDT) against C. albicans in vitro using a clinically approved photosensitizing agent. We propose to continue the in vitro studies using C. albicans biofilms, and evaluate the efficacy of PDT in an animal model of OPC. The central hypothesis is that the development of optimal parameters for PDT of C, albicans biofilms formed in vitro can be used to inform the development of a topical treatment of OPC in an experimental animal model. Specific aim 1: To assess the efficacy of selected photosensitizing agents in PDT of a Candida albicans biofilm. la. To compare the ability of selected PDT agents to photosensitize damage to optically irradiated C. albicans monolayers. Ib. To determine the spatial relationships between photosensitizing agent uptake, fluorescence spectroscopic signatures of photodynamic action, and organism damage in a C. albicans biofilm by laser scanning confocal fluorescence microscopy. Specific aim 2: To demonstrate proof of principle of PDT in the treatment of OPC in an animal model. 2a. To evaluate the distribution and retention of photosensitizing agents in C. albicans and surrounding normal tissue using in situ fluorescence imaging techniques in freshly excised tissue and in living animals. 2b. To demonstrate proof of principle of PDT in the treatment of C. albicans infection in the oral cavity of rats in vivo.